Tuberculosis (TB) remains a leading cause of death from infection due to challenges of compliance with multi- drug regimens lasting 6 months or longer and vulnerable populations including patients coinfected with HIV. Treatment shortening trials for TB have been disappointing. One way past this obstacle could be stimulating endogenous defense pathways to accelerate and enhance the response to antibiotics. The anti-diabetic drug metformin (MET) is a candidate host-directed therapy (HDT) agent for TB based on its activation of AMP kinase and induction of autophagy in macrophages. Our preclinical data in the mouse TB model and analysis of existing data on diabetic TB patients establish the HDT potential of MET. Notably, we found that MET expands M. tuberculosis antigen-specific CD8+ T cells that may have particular benefit for TB in AIDS. We plan a clinical trial in TB/HIV coinfecte patients to test the hypothesis that adding MET to standard directly observed treatment, short course (DOTS) antibiotic therapy increase the proportion of patients with a negative sputum culture at 2 months. To test this hypothesis, TB/HIV patients will be randomized to MET or placebo added to DOTS for the duration of TB treatment. Finding a significant effect of MET on month-2 sputum conversion would demonstrate its potential to enhance the efficacy of shortened TB treatment regimens. The Metformin for TB/HIV Host-directed Therapy (METHOD) trial will also test the effects of adjunctive MET on TB outcomes (cure, failure, death, default), radiographic severity, lung function as well as HIV viral load and the rate of immune reconstitution inflammatory syndrome. Conducting this HDT trial in HIV-coinfected patients focuses on the population in greatest need of a better approach to TB treatment and provides a rigorous test that would predict benefit for all patients with TB. Patient samples from this trial ill also be used to address fundamental questions about the mechanisms of HDT efficacy that may include control of harmful inflammation and expansion of CD8+ effector T cells in addition to the enhancement of lesion sterilization. A long range goal of this study component is to identify cost-effective biomarkers of treatment response that could be used in future HDT trials and potentially in clinical practice as guideposts for optimal TB treatment. In the current application we seek R34 funding to support all of the tasks needed to prepare a compelling UO1 application for the METHOD trial. This clinical trial development phase will involve the collaborative effort o future METHOD trial investigators from all three participating institutions and will position us fo the